Cardiac troponin T is not increased in patients with hypothyroidism.

Patients with hypothyroidism often have increased creatine kinase (CK) levels. It is possible that there is increased production of CK, but other mechanisms, such as an increased cell membrane permeability or decreased enzyme clearance were also proposed. Recently, troponins T and I have been extensively studied because of their cardiac specificity. Cardiac troponins are sensitive and specific markers of cardiac injury. The objective of the study was to measure cardiac troponin T (cTnT) levels in patients with hypothyroidism. Twenty-five patients with primary hypothyroidism were evaluated (thyroid-stimulating hormone (TSH) >30 mU/L and low FT(4)). In all patients thyrotropin (TSH), free thyroxine (FT(4)), CK, CK-MB and cTnT were measured.There were 3 men and 22 women with a mean age of 47.5 +/- 12.4 years. TSH levels ranged from 31 to 75 mIU/L and mean FT(4) levels were 4.5 +/- 1.9 pmol/L. CK was normal in 11 patients and increased in 14. CK levels ranged between 86 and 1221 U/L (normal levels <170 in women, <195 in men) with a mean of 322 U/L +/- 279. CK-MB was increased in 4 patients (16%) and normal in 21. All 25 patients had normal cTnT levels, < 0.01 ng/mL (normal levels 0-0.1 microg/L). Increase in CK and its MB fraction are common in patients with hypothyroidism but cTnT levels are not, even in patients with increased CK-MB. Therefore, cTnT is a reliable marker of cardiac injury even in the hypothyroid patient.

The thyroid hormone-αvß3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation.

Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvß3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvß3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvß3) and A2780 (low αvß3) cells promoted αv and ß3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvß3 antibodies, excluding T3-induced ß3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of ß3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvß3-deficient HEK293 cells treated with αvß3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the ß3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvß3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

Interleukin 1 beta mediates stress-induced immunosuppression via corticotropin-releasing factor.

Intracerebroventricular (icv) infusion of human interleukin 1 beta (IL-1) into intact and adrenalectomized rats impairs immune function. Using antibody to IL-1 as well as an inhibitor of IL-1 action, we sought to determine if endogenous IL-1 in the central nervous system has a physiological role in mediating the immunosuppressive effects of stress. Compared with freely moving controls, rats given intermittent electric shock to the tail for 40 min exhibited a fall in T lymphocyte proliferation and natural killer (NK) cell cytotoxicity of 33% and 38%, respectively; however, when pretreated with icv human IL-1 monoclonal antibody, which significantly crossreacts with rat IL-1, the decrement was attenuated to 14.6% and 15%, respectively. When rats were pretreated with icv alpha-MSH, which blocks many IL-1 effects, shock-induced suppression of 42% in both T lymphocyte proliferation and NK cytotoxicity were blunted to 33% and 31%, respectively. Similar results were found in adrenalectomized rats. These findings suggest that endogenous IL-1 is a physiologically relevant mediator of the immune response to stress. As IL-1 has been reported to release CRF, which we have shown always plays a significant role in stress-induced immunomodulation, we then assessed the relationship of IL-1 and CRF in immunosuppression. Infusion of icv IL-1 caused a decrease of 35% in T lymphocyte proliferation and 34% in NK activity, but pretreatment with CRF antibody icv attenuated IL-1 suppression of T lymphocyte proliferation and NK activity to 10% and 8%, respectively. Comparable results were observed in adrenalectomized rats. These findings suggest that CRF antibody is able to block the immunosuppressive effects of IL-1. To further examine the interaction of CRF in mediating stress-induced immunosuppression, we found that animals pretreated with icv CRF antibody, shocked and then given icv IL-1, had a decrement in T lymphocyte proliferation and NK cytotoxicity of 24% and 21%, respectively, demonstrating that the immunosuppressive effect of icv IL-1 is blocked when central CRF has been neutralized by prior administration of icv CRF antibody. In contrast, animals pretreated with icv IL-1 antibody, shocked and then given icv CRF, had decrements of 38% and 40%, respectively, showing that icv CRF does act even when central IL-1 has been neutralized by prior administration of icv IL-1 antibody. Thus, we conclude there is a sequential relationship between two of the known mediators of stress-induced immunosuppression, with release of central IL-1 followed by that of CRF.

Sarcoidosis masquerading as a parathyroid adenoma.

Two patients presented with a presumptive diagnosis of hyperparathyroidism. Surgically excised "parathyroid glands" were found to be, in fact, large lymph nodes with sarcoid granulomata. In one patient, the preoperative localization of the "parathyroid adenoma" was based on scintigraphy (thallium-technetium subtraction imaging) and sonography procedures. The differential diagnosis of hypercalcemia, and positive scintigraphy-sonography studies, must include sarcoidosis in an isolated cervical lymph nodes.

Autoimmune thyroid disease and antiphospholipid antibodies.

OBJECTIVE: Autoimmune thyroid disease (ATD) is associated with circulating autoantibodies reactive with epitopes on thyroid tissue and that are thought to be pathogenic in the development of these diseases. Antiphospholipid antibodies (APLA) are a family of immunoglobulins that recognize a variety of plasma proteins in association with anionic phospholipids. These antibodies may lead to a number of clinical syndromes including venous and arterial thromboses, thrombocytopaenia, and recurrent fetal loss. We have studied the prevalence of APLA in patients with ATD and have determined the prevalence of the APLA syndrome among APLA-positive patients. DESIGN: The study was a retrospective survey of patients with autoimmune thyroid disease attending the endocrinology clinic of a tertiary care academic hospital. PATIENTS AND MEASUREMENTS: One hundred and thirty patients with autoimmune thyroid disease from the endocrinology clinic at our hospital were studied. 84% had chronic thyroiditis and 16% had Graves' disease. Free T4 and thyroid stimulating hormone (TSH) levels, antimicrosomal and antithyroglobulin antibodies, and an antiphospholipid antibody test were performed on all subjects. RESULTS: 43% of patients with chronic thyroiditis and 43% of patients with Graves' disease were APLA positive, with an overall rate of 43% APLA positivity among patients with ATD. Of the 56 patients that were APLA positive, forty-eight (86%) had APLA of the IgG subtype, four (7%) had IgM antibodies, and nine (16%) had both IgG and IgM antibodies. None of the patients had clinical evidence of the APLA syndrome. CONCLUSIONS: We conclude that the prevalence of APLA in ATD is increased compared to healthy individuals but that this is likely to be an epiphenomenon. However, prolonged follow up is necessary in order to determine the true clinical significance of these antibodies in ATD patients.

Clinical relevance of non-palpable thyroid nodules as assessed by ultrasound-guided fine needle aspiration biopsy.

It is known from autopsy data that thyroid nodules are far more common than can be detected by palpation alone. With the wide use of modern non-invasive imaging many non-palpable thyroid nodules are discovered but the proper approach to these nodules is still debatable. In a retrospective study, we reviewed the data from 186 US-guided FNA biopsies (US-FNAB) performed between May 1995 and March 1997 at the Sapir Medical Center, Israel, a iodine-sufficient urban area. Sixty-one of the 186 US-FNAB of the thyroid were performed in non-palpable nodules. The mean size of these nodules was 2.4 +/- 1.0 cm (mean +/- SD) ranging from 1.1-5.5 cm. Description of the nodule consistency was available in 53 cases; 42/53 were solid and 11/53 were solid-cystic. FNAB was diagnostic in 46 patients and non-diagnostic in 15. Forty-three of the diagnostic cytology reports were benign, one revealed papillary carcinoma, one had suspicious findings and the third was suspicious for a follicular neoplasm. The last two patients were referred to surgery and a follicular adenoma was found in both. Among the 61 non-palpable thyroid nodules, only one was papillary carcinoma, a prevalence of 1.6%. The other two patients referred to surgery had benign lesions. We found a low prevalence of malignancy in relatively large non-palpable thyroid nodules.

Adrenal insufficiency in a general hospital over a 14-year period.

Over a 14-year period, 26 patients with adrenal insufficiency of multiple etiology were evaluated. Eight were diagnosed at autopsy, six of whom had acute bilateral adrenal hemorrhage. Nine had chronic adrenal insufficiency. Of these, five were idiopathic and three had polyglandular disorders. Four others had tuberculosis. Six of nine patients with chronic adrenal insufficiency were hyperpigmented. Unusual manifestations of adrenal hypocorticism included hypercalcemia, flaccid paralysis, and joint contractures. The presence of multiple hormonal deficiencies focused the diagnosis on hypopituitarism. Two cases of isolated ACTH deficiency were detected. Patients with familial Mediterranean fever with amyloidosis commonly presented with reduced adrenal reserve rather than overt insufficiency. Metastatic cancer of the adrenal glands was a rare cause of reduced adrenal reserve.